Sustained drug release composition

ABSTRACT

The invention relates to a sustained release formulation for delivering one or more pharmaceutically active agents. The formulation comprises cross-linked high amylose starch and at least one pharmaceutically active agent, and optionally can be subdivided into smaller dosage forms where the smaller dosage forms have substantially the same sustained release properties as the formulation from which they were derived. The formulations can provide sustained release for up to at least 24 hours, and because of their divisability permits a recipient of the active agent or the person administering the active agent to titrate the dosage of the agent.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/519,189, filed Sep. 11, 2006, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/715,162, filed Sep. 9, 2005,the entire disclosures of each of which are incorporated by referenceherein.

FIELD OF THE INVENTION

The present invention relates generally to a sustained release drugcomposition and more particularly to a sustained release drugcomposition, which when subdivided into smaller dosage forms, thesmaller dosage forms display substantially the same drug release profileas the composition from which they were derived.

BACKGROUND

Typically, oral dosage forms for the delivery of pharmaceutically activeagents or drugs release the agent during passage through thegastrointestinal tract. The part of the gastrointestinal tract to whichthe active agent is delivered depends in part on the type of deliverysystem involved. Certain delivery systems release the active substancerapidly, leading to, for example, a rapid rise to a maximumconcentration of drug in the blood usually followed by a rapid decreasein concentration as the drug is cleared from the body. If the drugconcentration rises and/or decreases rapidly, this may create a narrowwindow of time during which the drug is therapeutically effective. As aresult, sustained therapeutic efficacy may require administration ofmultiple, sequential doses of the drug. In addition, if release of drugto the body is uncontrolled in this manner, adverse events associatedwith the drug may not be controllable and the drug may not beeffectively delivered to the site requiring treatment.

Various compositions and dosage forms have been used to control drugrelease and thereby provide sustained release of active agents toprovide sustained efficacy from one composition. For example, awell-known way of controlling the release of drug is to apply a coatingto a solid core. For example, a polymer coating can produce a ratecontrolling film on the surface of the core. The release rate of thetherapeutic agent can then be altered by factors including the thicknessof the coating, the diffusivity of agent, through the coating, and therate of biodegradation of the coating. If the coated dosage form isbroken, or damaged, during or after administration, the coating may nolonger provide an effective rate controlling film resulting in the drugbeing rapidly released from the core.

Drug dosing regimens, be they acute or chronic, may vary from patient topatient. Different patients can have different therapeutic responses toa given dose of drug. Further, physicians sometimes start with a smallerthan recommended dose of a drug and titrate the dose upward over time tominimize, for the patient, the frequency and severity of adverse eventsassociated with optimum blood concentrations of the drug. Alternatively,for some patients and/or drug therapies, physicians start with a high,or loading dose of drug to achieve maximum and rapid therapeutic benefitand then reduce the dose administered to maintain efficacy. Such dosingregimens require precise control over the dosage administered, which,with the right formulation, can be achieved using for example, a singletablet that may be sub-divided into subunits each having a smaller doseof the drug, where each of the subunits delivers the drug in the samemanner as the tablet from which they were derived.

There is a need, therefore, for a formulation of a pharmaceuticallyactive agent, which when sub-divided or broken into smaller dosage formsachieves substantially the same sustained release profile as theoriginal formulation, and which conveniently permits modification ofdosing regimens.

SUMMARY OF THE INVENTION

The invention provides solid, sustained drug release dosage forms thatcan be subdivided into smaller dosage forms. The smaller dosage formsprovide substantially the same drug release kinetics as the solid dosageform they were created from. The formulations provided herein permit arecipient, a treating physician, or a person administering the drug, toconveniently create smaller dosage forms that can be used to moreaccurately and precisely deliver the appropriate amount of drug to therecipient.

In one aspect, the invention provides a solid, monolithic sustainedrelease pharmaceutical composition comprising: (a) a sustained releasematrix having a solvent accessible surface, wherein the matrix comprisescross-linked high amylose starch; and (b) an effective amount of atleast one pharmaceutically active agent disposed within the matrix. Thecomposition has a hardness of greater than about 100 N, for example, inthe range from about 100N to about 350 N.

Such a composition, when administered to a mammal, for example, a human,achieves an effective plasma concentration, for example, atherapeutically effective plasma concentration of the active agent fromat least about 1 hour to at least about 24 hours after initialadministration. The composition comprises a solvent accessible surfacethat optionally defines a score or scores, which permits the compositionto be sub-divided along the score to produce at least two subunits eachhaving a new solvent accessible surface. At least one of the resultingsubunits has substantially the same release kinetics of the active agentas the intact composition from which it was derived. Furthermore, thedissolution profiles of at least one of the subunits and the compositionfrom which it was derived have a similarity factor of at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, andat least 80%.

In another aspect, the invention provides a solid sustained releasepharmaceutical composition comprising: (a) a sustained release matrixhaving a solvent accessible surface, wherein the matrix comprisescross-linked high amylose starch; and (b) an effective amount of apharmaceutically active agent disposed within the matrix The composition(i) displays substantially the same release kinetics when thecomposition is broken or subdivided along a score, to create a newsolvent accessible surface, and/or (ii) can be divided into at least twosubunits where each subunit releases the active agent with substantiallythe same release profile as the composition from which they werederived.

The composition has a hardness of greater than about 100 N, and, forexample, has a hardness in the range from about 100 N to about 350 N.Such a composition can be monolithic in nature. The new solventaccessible surface created by dividing or breaking the original dosageform, and like the original solvent accessible surface of the originalintact form, can form a barrier having membrane-like properties whenexposed to an aqueous solvent.

The dissolution profiles of at least one subunit and the compositionfrom which it was derived have a similarity factor of at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, andat least 80%. The subunits and the intact composition from which theyare derived can be designed to be bioequivalent, and each subunit canrelease the active agent for at least about 12 hours, about 18 hours, orat least 24 hours.

The compositions described herein comprise from about 15% to about 60%by weight of the active ingredient and from about 15% to about 85% byweight of a controlled release excipient that defines the sustainedrelease matrix, from about 20% to about 50% by weight of the activeingredient and from about 20% to about 50% by weight of the controlledrelease excipient, and from about 35% to about 50% by weight of theactive ingredient and from about 20% to about 50% by weight of thecontrolled release excipient.

It is contemplated that a number of different controlled releaseexcipients may be useful in the practice of the invention. Thecontrolled release excipients comprise cross-linked high amylose starch.In certain embodiments, the cross-linked high amylose starch is crosslinked with phosphorus oxychloride and/or comprises hydroxypropyl sidechains. In certain other embodiments, the cross-linked high amylosestarch comprises between about 65% and about 75% by weight of amyloseand is cross-linked with phosphorus oxychloride. One preferredcross-linked high amylose starch useful in the practice of the inventionis known as CONTRAMID® cross-linked, high amylose starch, availablecommercially from Labopharm, Inc., Laval, Canada.

It is contemplated that a number of different pharmaceutically activeagents can be incorporated into the compositions and dosage forms of theinvention. Such active agents can include, for example, antidepressants,for example, trazodone, and analgesics, for example, tramadol andacetaminophen or combinations thereof. It is contemplated that one, two,three or more active agents can be incorporated into the formulationsdescribed herein.

In addition, the sustained release pharmaceutical composition optionallyincludes one or more pharmaceutical additives. Exemplary pharmaceuticaladditives include binding agents (for example,hydroxypropylmethylcellulose), solubilizing agents (for example,povidone or cetylpyridinium chloride), acidifying agents (for example,alginic acid), pore forming agents (for example, sucrose), lubricants(for example, sodium stearyl fumarate), and glidants (for example,colloidal silicon dioxide).

The sustained release pharmaceutical composition can be formulated intoa variety of shapes and forms such as tablets and caplets suitable fororal administration. In one embodiment, the invention provides a caplet.Such tablets and caplets can be scored on one or both sides, and/or havemultiple scores.

Also provided are methods of making the formulations described herein aswell as methods of using such formulations.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated but is not limited by the annexed drawings,in which

FIG. 1 is a schematic representation of an exemplary formulation of theinvention;

FIG. 2 is a graph illustrating the in vitro dissolution profile of anintact tablet (▴) compared to a bisected tablet (◯) of an exemplary 300mg formulation of trazodone;

FIG. 3 is a graph illustrating the in vitro dissolution profile of anintact tablet of an exemplary formulation containing 300 mg trazodone(●) with a bisect depth score of 23% of the tablet cup depth and asubdivided tablet (◯) derived from an intact tablet with the samescoring;

FIG. 4 is a graph illustrating the in vitro dissolution profile of anintact tablet of an exemplary formulation containing 300 mg trazodone(●) with a bisect depth score of 95% of the tablet cup depth and asubdivided tablet (◯) derived from an intact tablet with the samescoring;

FIG. 5 is a graph illustrating the test for uniformity of mass on anexemplary tablet formulation containing 150 mg trazodone where ahardness of 111 N is required to achieve a relative standard deviation(RSD) of less than 6% as required by the U.S.P.; and

FIG. 6 is a graph illustrating the in vitro dissolution profile of anintact tablet (▴) compared to a bisected tablet (◯) of an exemplary 150mg formulation of trazodone;

FIG. 7 is a graph illustrating the in vitro dissolution profile of anintact tablet (▴) compared to a bisected tablet (◯) of an exemplary 300mg formulation of tramadol.

DETAILED DESCRIPTION

The invention is based, in part, upon the discovery that it is possibleto formulate a sustained release composition, which when sub-divided,e.g., broken or separated into subunits or smaller dosage forms, atleast one of the resulting subunits or smaller dosage forms hassubstantially the same drug release profile as the original intactcomposition from which it was derived. Such a sustained releasecomposition, whether sub-divided or intact, provides a rate of releaseof active agent that is controlled over a period of time up to about 12hours, up to about 18 hours, or up to about 24 hours, or more. Afteradministration of such a sustained release composition, the drug plasmaconcentration of a patient may be controlled, e.g., up to 12 hours, upto 18 hours, and 24 hours. This discovery was surprising because ifsub-divided (broken or separated into subunits), sustained or controlledrelease compositions can lose their sustained release properties, i.e.,the subunits deliver the active agent in a rapid and uncontrolledfashion.

Accordingly, in one aspect the invention provides a solid, monolithicsustained release pharmaceutical composition comprising: (a) a sustainedrelease matrix having a solvent accessible surface, wherein the matrixcomprises cross-linked high amylose starch; and (b) an effective amountof at least one pharmaceutically active agent disposed within thematrix. The composition has a hardness of greater than about 100 N, forexample, in the range from about 100N to about 350 N.

As used herein, the term “effective amount” can include therapeuticallyeffective amounts and amounts suitable for titration regimens and thelike, where, for example, multiple tablets or subdivided tablets need tobe administered to an individual to achieve a maximum therapeuticefficacy with minimizing adverse effects.

The term “therapeutic effect” is art-recognized and refers to a local orsystemic effect in animals, particularly mammals, and more particularlyhumans caused by a pharmacologically active substance. The term thusmeans any substance intended for use in the diagnosis, cure, mitigation,treatment or prevention of disease or in the enhancement of desirablephysical or mental development and/or conditions in an animal or human.The phrase “therapeutically-effective amount” means that amount of sucha substance that produces some desired local or systemic effect at areasonable benefit/risk ratio applicable to any treatment. Thetherapeutically effective amount of such substance will vary dependingupon the subject and disease condition being treated, the weight and ageof the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. For example, certain compositions of thepresent invention may be administered in a sufficient amount to producean amount at a reasonable benefit/risk ratio applicable to suchtreatment.

In another aspect, the invention provides a solid sustained releasepharmaceutical composition comprising: (a) a sustained release matrixhaving a solvent accessible surface, wherein the matrix comprisescross-linked high amylose starch; and (b) an effective amount of apharmaceutically active agent disposed within the matrix The composition(i) displays substantially the same release kinetics when thecomposition is sub-divided by breaking or fracturing to create a newsolvent accessible surface, and/or (ii) can be divided into at least twosubunits where each subunit releases the active agent with substantiallythe same release profile as the composition from which it was derived.

These formulations may be monolithic in nature. As used herein, the term“monolithic” is understood to mean a composition that releases an activeagent in a substantially uniform fashion, with the compositiondissolving or disintegrating substantially uniformly, rather than inlayers.

The foregoing compositions have hardness of greater than about 100 N.The compositions typically have a hardness in the range from about 110 Nto about 350 Accordingly, the compositions optionally can have ahardness of 110 N, 120N, 140N or higher. Preferred hardnesses range fromabout 100 N to about 180N, or from 110N to about 140N, or about 140 N toabout 180 N. For example, the hardness may vary depending on the size ofthe tablet, e.g. a smaller tablet may have a hardness of about 100 N toabout 140 N; a larger tablet may have a hardness of about 220 N to 260N. As used herein, the term “hardness” is used to describe the diametralbreaking strength as measured by conventional pharmaceutical hardnesstesting equipment. Preferably, such compression is performed in a singleprocess.

The sustained release matrices include a controlled release excipient.The composition comprises from about 15% to about 60% by weightpharmaceutically active agent, and from about 15% to about 85% by weightpercent of a controlled release excipient. The controlled releaseexcipient, when orally administered to a mammal, for example, a person,permits the pharmaceutically active agent to achieve and/or maintaineffective and/or controlled plasma concentrations, for example, aneffective plasma concentration for up to about 24 hours after initialadministration. Such release kinetics are substantially the same when anintact composition, e.g., a tablet is broken, separated or sub-dividedinto subunits.

As shown in FIG. 1, an exemplary solid sustained release composition 10includes (i) a sustained release matrix having an interior or core 20and a solvent accessible surface 30, and (ii) a pharmaceutically activeagent 40 disposed therein. The sustained release matrix includes acontrolled release excipient, such as cross-linked high amylose starch.When the composition, such as a solid dosage form, is fractured ordivided, to produce subunits 60, each subunit contains a portion of theoriginal solvent accessible surface 30 and a newly exposed solventaccessible surface 70. Without wishing to be bound by theory, thecontrolled release excipient, e.g., cross-linked high amylase starch,may form a membrane e.g. a semi-permeable membrane, or barrier layer,which may be, for example, over, on, or constitute part of the solventaccessible surface (30 and 70). Such a barrier may contribute tosubstantially stable release kinetics of the active agent in thesub-divided or intact forms.

The intact solid sustained release composition 10 optionally comprisesone or more scores 50, shown in phantom in FIG. 1. The scores can beused to guide the subdivision of the intact tablet. Although FIG. 1shows a tablet with two adjacent scores, however, it is contemplatedthat the tablet can contain more scores if more than two subunits aredesired.

Accordingly, the invention provides a sustained release solid dosageform comprising cross-linked high amylose starch and a pharmaceuticallyactive agent, wherein the solid dosage form can be separated intosubunits, with each subunit having substantially the same sustainedrelease properties as the intact or unbroken solid dosage form. Dosageforms may be bisected, e.g., divided into two substantially equalpieces, or may be divided into other fractional sections, e.g., thirdsor fourths. Dosage forms may also be divided into unequal sections,e.g., one-third/two-thirds.

In vitro dissolution profiles of intact and separated sustainedformulations as described herein may be compared using fit factors orother mathematical comparisons. Such fit factors are known to thoseskilled in the art and are used to predict bioequivalency of differentdosage forms. The fit factor f₁ represents relative error between twocurves, or in other words, the mean relative difference on all measuredpoints. Fit factor f₁ is sometimes referred to as the difference factor.The mean relative difference for each sample point should be betweenabout 0 to about 15% for bioequivalence. In some embodiments,compositions and/or formulations may have a similarity factors betweenan intact dosage form and subunits of the intact dosage form of lessthan about 15%, less than about 10%, or less than about 7%. The fitfactor f₂ is a logarithmic transformation of the mean of squaresdifferences between two curves. Fit factor f₂ is sometimes referred toas the similarity factor. The similarity factor should be between about50% and about 100% for bioequivalence, e.g., between the subunit formsand intact dosage forms. In some embodiments, compositions and/orformulations can have similarity factors between an intact dosage formand the subunits derived from the intact dosage form of at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, andat least 80%.

The formulations described herein can provide rise in plasmaconcentrations of the active ingredient, which thereafter remainrelatively and substantially stable for at least 10, at least 12, atleast 18, or at least 24 hours or more, regardless of whether the dosageform is separated into subunits or is in an intact form. The plasmaconcentration between one hour and 24 hours may remain within about 45%of the mean plasma concentration, more preferably between about 30% ofthe mean, and most preferably between about 15% of the mean plasmaconcentration. In certain formulations, after an initial rapid releaseof the active agent, within an hour of ingestion the active agent isreleased in vivo with approximately zero order kinetics for at leastabout 24 hours, leading to plateau plasma concentrations.

Dosages in a particular sustained release formulation can vary to alarge extent depending on required needs of the patient, and thespecific requirements of the treating physician. For example, the dosageof any compositions of the present invention will vary depending on thesymptoms, age and body weight of the patient, the nature and severity ofthe disorder to be treated or prevented, the route of administration,and the form of the subject composition. Dosages for the compositions ofthe present invention may be readily determined by techniques known tothose of skill in the art or as taught herein. The precise time ofadministration and amount of any particular subject composition thatwill yield the most effective treatment in a given patient will dependupon the activity, pharmacokinetics, and bioavailability of a subjectcomposition, physiological condition of the patient (including age, sex,disease type and stage, general physical condition, responsiveness to agiven dosage and type of medication), route of administration, and thelike. The guidelines presented herein may be used to optimize thetreatment, e.g., determining the optimum time and/or amount ofadministration, which will require no more than routine experimentationconsisting of monitoring the subject and adjusting the dosage and/ortiming.

Specific sustained dosages can be tailored using the dosage forms bybreaking the dosage forms disclosed herein into substantially similarbut smaller doses having substantially similar sustained releaseprofiles. For example, smaller doses may be useful for patients lighterin weight and/or for paediatric use. Alternatively, one dosage may beprovided, but in a smaller form that may be more acceptable to apatient. For example, a patient may be able to divide a dosage intoeasier-to-swallow components while still maintaining the sustainedrelease properties of the dosage form. The ability to alter dosage on apatient by patient basis with one dosage form may also be convenientfor, e.g., a physician or a pharmacist.

For some patients, a typical recommended dose may be larger than what isneeded, increasing the chance of adverse effects. For example, patientstaking tramadol, reported adverse reactions include dizziness, nauseaand constipation. Reported adverse effects for trazodone formulationsinclude dizziness, dry-mouth, nervousness and fatigue. Patients takingbetahistidine have reported gastric upset, nausea and headache.

One approach for decreasing adverse effects is dose titration. Forexample, for patients that do not require an immediate response, a dosethat is about one-fourth to one-half the recommended dose may beinitially administered and over a course of a time, e.g., two to fourweeks, the dose may be titrated or increased until the desired effect isobtained. For acute conditions, titration can occur over the course ofdays, rather than weeks. The disclosed dosage forms may used in suchdose titration regimens, for example, by dividing an intact form intosub-sections that can be taken individually for smaller doses and thentaken in larger sub-sections or intact forms for larger doses. Dosetitration is often used, for example, in the administration ofanalgesics such as opioids to achieve pain relief while maintaining anacceptable level of adverse side effects.

The disclosed dosage forms may used in such dosage regimens that startwith, e.g., the recommended dose, and subsequently have reduced dosagesaccording to the patient's needs. For example, such a regimen may beaccomplished by administring an intact dosage form as disclosed hereinand then dividing an intact form into subunits, each of which can betaken individually for smaller doses.

The composition according to the invention is normally prepared in theform of a tablet. Although the tablet can adopt a wide variety of shapesas is well known to those skilled in the art, the preferred shape is acaplet. Such caplets may be formed, for example, with compositionincluding a controlled release excipient and at least one active agentand using upper and lower punches set in a tableting machine as is knownin the art. In some embodiments, tablets may include a coating, such as,for example, an inert coating containing a colorant. Suitable coatingsinclude, for example, aqueous film coating polymers such as polyvinylalcohol, talc, macrogel and the like, and mixtures thereof. Suitablecolorants include, for example, iron oxides, lakes, natural colorantsand other colorants known to those skilled in the art. Preferably, sucha coating does not affect the release kinetics, e.g. dissolutionperformance of a dosage form when intact or when sub-divided.

In some embodiments, the dosage forms, e.g., tablets, may be scored.Preferably, scored tablets or un-scored tablets are broken with highbreaking accuracy thereby ensuring matching or proportional releaseprofiles from each resultant sub-division. Breaking accuracy maydetermined for example, by evaluating the mass uniformity of separated,e.g., bisected, parts of the same tablet. The mass uniformity of atablet may be determined in terms of relative standard deviation (RSD)from the mean mass of tablet sections using the U.S.P. test limit ofuniformity (RSD below 6%). FIG. 5 indicates, for the exemplaryformulation as described in Example 2, hereinbelow, that for such aformulation, the minimum tablet hardness needed for mass uniformity withan RSD below 6% is about 110 N.

Scoring may have varying depths, e.g., from about 0% (e.g., no scoring)to about 95% of the tablet cup depth. Each tablet may have one, two, ormultiple scores, and/or scoring on one or both sides of the tablet. Ascan be seen in Example 1, hereinbelow, scoring does not substantiallyaffect the release profiles of the tablets when intact or when brokenalong the score.

The formulations may have in vitro profiles as described in the Exampleshereinbelow. The in vitro release profiles can be measured using theU.S.P. paddle method (apparatus type II as described in U.S.P. XXVI) at150 revolutions per minute, at 37±0.5° C., in 900 mL ofhydrochloride/sodium chloride pH 1.2 solution (acid stage) followedafter one hour by 900 mL of sodium phosphate monobasic buffer pH 6.0(buffer stage). In some embodiments, formulations may have releasekinetics, whereby, when tested by the foregoing method, not more thanabout 30% of the active ingredient is released by 1 hour afterinitiation of the experiment, about 35% to 55% of the active ingredientis released by 6 hours, not more than about 80% of the active ingredientis released by 12 hours, and/or not less than about 80% of the activeingredient is released by 24 hours.

Formulations contemplated herein may reach steady-state, for example,on-average, within a normal population, after about the fourthadministration. The peak-to-trough ratio produced by such formulationsat steady-state may be about 60% to about 100%.

The formulations described herein are particularly useful in thedelivery of pharmaceutically active agents and their derivatives.Derivatives include pharmaceutically acceptable pro drugs, metabolites,salts and esters, or the like. For example, the term“pharmaceutically-acceptable salts” is art-recognized and refers to therelatively non-toxic, inorganic and organic acid addition salts ofcompounds, including, for example, those contained in compositions ofthe present invention.

The term “pharmaceutically active agent” refers to any chemical moietythat is a biologically, physiologically, or pharmacologically activesubstance that acts locally or systemically in a subject. Examples ofpharmaceutically active agents, also referred to herein as “drugs,” aredescribed in well-known literature references such as the Merck Index,the Physicians Desk Reference, and The Pharmacological Basis ofTherapeutics, and they include, without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of a disease or illness;substances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a physiological environment.

Compositions and formulations contemplated herein may include one ormore pharmaceutically active agents. For example, a composition mayinclude two, three or more different pharmaceutically active agents.

The pharmaceutically active substance of the invention can vary widelywith the purpose for the composition. It is contemplated that one or aplurality of different pharmaceutically active agents are included inthe formulations described herein. Non-limiting examples of broadcategories of useful pharmaceutically active agents include thefollowing therapeutic categories: anabolic agents, antacids,anti-asthmatic agents, anti-cholesterolemic and anti-lipid agents,anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics,anti-infective agents, anti-inflammatory agents, anti-manic agents,anti-nauseants, anti-neoplastic agents, anti-obesity agents,anti-pyretic and analgesic agents, anti-spasmodic agents,anti-thrombotic agents, anti-uricemic agents, anti-anginal agents,antihistamines, anti-tussives, appetite suppressants, biologicals,cerebral dilators, coronary dilators, decongestants, diuretics,diagnostic agents, erythropoietic agents, expectorants, gastrointestinalsedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ionexchange resins, laxatives, mineral supplements, mucolytic agents,neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives,stimulants, thyroid and anti-thyroid agents, uterine relaxants,vitamins, and pro-drugs.

More specifically, non-limiting examples of useful pharmaceuticallyactive substances include the following therapeutic categories:analgesics, such as nonsteroidal anti-inflammatory drugs, opiateagonists and salicylates; antihistamines, such as H₁-blockers andH₂-blockers; anti-infective agents, such as anthelmintics,antianaerobics, antibiotics, aminoglycoside antibiotics, antifungalantibiotics, cephalosporin antibiotics, macrolide antibiotics,miscellaneous β-lactam antibiotics, penicillin antibiotics, quinoloneantibiotics, sulfonamide antibiotics, tetracycline antibiotics,antimycobacterials, antituberculosis antimycobacterials, antiprotozoals,antimalarial antiprotozoals, antiviral agents, antiretroviral agents,scabicides, and urinary anti-infectives; antineoplastic agents, such asalkylating agents, nitrogen mustard alkylating agents, nitrosoureaalkylating agents, antimetabolites, purine analog antimetabolites,pyrimidine analog antimetabolites, hormonal antineoplastics, naturalantineoplastics, antibiotic natural antineoplastics, and vinca alkaloidnatural antineoplastics; autonomic agents, such as anticholinergics,antimuscarinic anticholinergics, ergot alkaloids, parasympathomimetics,cholinergic agonist parasympathomimetics, cholinesterase inhibitorparasympathomimetics, sympatholytics, α-blocker sympatholytics,β-blocker sympatholytics, sympathomimetics, and adrenergic agonistsympathomimetics; cardiovascular agents, such as antianginals, β-blockerantianginals, calcium-channel blocker antianginals, nitrateantianginals, antiarrhythmics, cardiac glycoside antiarrhythmics, classI antiarrhythmics, class II antiarrhythmics, class III antiarrhythmics,class IV antiarrhythmics, antihypertensive agents, α-blockerantihypertensives, angiotensin-converting enzyme inhibitor (ACEinhibitor) antihypertensives, β-blocker antihypertensives,calcium-channel blocker antihypertensives, central-acting adrenergicantihypertensives, diuretic antihypertensive agents, peripheralvasodilator antihypertensives, antilipemics, bile acid sequestrantantilipemics, HMG-COA reductase inhibitors, antilipemics, inotropes,cardiac glycoside inotropes, and thrombolytic agents; dermatologicalagents, such as antihistamines, anti-inflammatory agents, corticosteroidanti-inflammatory agents; electrolytic and renal agents, such asacidifying agents, alkalinizing agents, diuretics, carbonic anhydraseinhibitor diuretics, loop diuretics, osmotic diuretics,potassium-sparing diuretics, thiazide diuretics, electrolytereplacements, and uricosuric agents; enzymes, such as pancreatic enzymesand thrombolytic enzymes; gastrointestinal agents, such asantidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents,salicylate gastrointestinal anti-inflammatory agents, antacid anti-ulceragents, gastric acid-pump inhibitor anti-ulcer agents, gastric mucosalanti-ulcer agents, H₂-blocker anti-ulcer agents, cholelitholytic agents,digestants, emetics, laxatives and stool softeners, and prokineticagents; hematological agents, such as antianemia agents, hematopoieticantianemia agents, coagulation agents, anticoagulants, hemostaticcoagulation agents, platelet inhibitor coagulation agents, thrombolyticenzyme coagulation agents, and plasma volume expanders; hormones andhormone modifiers, such as abortifacients, adrenal agents,corticosteroid adrenal agents, androgens, anti-androgens, antidiabeticagents, sulfonylurea antidiabetic agents, antihypoglycemic agents, oralcontraceptives, progestin contraceptives, estrogens, fertility agents,oxytocics, parathyroid agents, pituitary hormones, progestins,antithyroid agents, thyroid hormones, and tocolytics; immunobiologicagents, such as immunoglobulins, immunosuppressives, toxoids, andvaccines; local anesthetics, such as amide local anesthetics and esterlocal anesthetics; musculoskeletal agents, such as anti-goutanti-inflammatory agents, corticosteroid anti-inflammatory agents, goldcompound anti-inflammatory agents, immuno-suppressive anti-inflammatoryagents, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylateanti-inflammatory agents, skeletal muscle relaxants, neuromuscularblocker skeletal muscle relaxants, and reverse neuromuscular blockerskeletal muscle relaxants; neurological agents, such as anticonvulsants,barbiturate anticonvulsants, benzodiazepine anticonvulsants,anti-migraine agents, anti-parkinsonian agents, anti-vertigo agents,opiate agonists, and opiate antagonists; sychotropic agents, such asantidepressants, heterocyclic antidepressants, monoamine oxidaseinhibitors (MAOIs), selective serotonin re-uptake inhibitors (SSRIs),tricyclic antidepressants, antimanics, antipsychotics, phenothiazineantipsychotics, anxiolytics, sedatives, and hypnotics, barbituratesedatives and hypnotics, benzodiazepine anxiolytics, sedatives, andhypnotics, and psychostimulants; respiratory agents, such asantitussives, bronchodilators, adrenergic agonist bronchodilators,antimuscarinic bronchodilators, expectorants, mucolytic agents,respiratory anti-inflammatory agents, and respiratory corticosteroidanti-inflammatory agents; toxicology agents, such as antidotes, heavymetal antagonists/chelating agents, substance abuse agents, deterrentsubstance abuse agents, and withdrawal substance abuse agents; minerals;and vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D,vitamin E, and vitamin K.

Preferred classes of useful pharmaceutically active agents from theabove categories include: (1) nonsteroidal anti-inflammatory drugs(NSAIDs) analgesics, such as diclofenac, ibuprofen, ketoprofen, andnaproxen; (2) opiate agonist analgesics, such as codeine, fentanyl,tramadol, hydromorphone, and morphine; (3) salicylate analgesics, suchas aspirin; (4) H1-blocker antihistamines, such as clemastine andterfenadine; (5) H2-blocker antihistamines, such as cimetidine,famotidine, nizadine, and ranitidine; (6) anti-infective agents, such asmupirocin; (7) antianaerobic anti-infectives, such as chloramphenicoland clindamycin; (8) antifungal antibiotic anti-infectives, such asamphotericin b, clotrimazole, fluconazole, and ketoconazole; (9)macrolide antibiotic anti-infectives, such as azithromycin anderythromycin; (10) miscellaneous β-lactam antibiotic anti-infectives,such as aztreonam and imipenem; (11) penicillin antibioticanti-infectives, such as nafcillin, oxacillin, penicillin G, andpenicillin V; (12) quinolone antibiotic anti-infectives, such asciprofloxacin and norfloxacin; (13) tetracycline antibioticanti-infectives, such as doxycycline, minocycline, and tetracycline;(14) antituberculosis antimycobacterial anti-infectives such asisoniazid (INH), and rifampin; (15) antiprotozoal anti-infectives, suchas atovaquone and dapsone; (16) antimalarial antiprotozoalanti-infectives, such as chloroquine and pyrimethamine; (17)anti-retroviral anti-infectives, such as ritonavir and zidovudine; (18)antiviral anti-infective agents, such as acyclovir, ganciclovir,interferon alfa, and rimantadine; (19) alkylating antineoplastic agents,such as carboplatin and cisplatin; (20) nitrosourea alkylatingantineoplastic agents, such as carmustine (BCNU); (21) antimetaboliteantineoplastic agents, such as methotrexate; (22) pyrimidine analogantimetabolite antineoplastic agents, such as fluorouracil (5-FU) andgemcitabine; (23) hormonal antineoplastics, such as goserelin,leuprolide, and tamoxifen; (24) natural antineoplastics, such asaldesleukin, interleukin-2, docetaxel, etoposide (VP-16), interferonalfa, paclitaxel, and tretinoin (ATRA); (25) antibiotic naturalantineoplastics, such as bleomycin, dactinomycin, daunorubicin,doxorubicin, and mitomycin; (26) vinca alkaloid natural antineoplastics,such as vinblastine and vincristine; (27) autonomic agents, such asnicotine; (28) anticholinergic autonomic agents, such as benztropine andtrihexyphenidyl; (29) antimuscarinic anticholinergic autonomic agents,such as atropine and oxybutynin; (30) ergot alkaloid autonomic agents,such as bromocriptine; (31) cholinergic agonist parasympathomimetics,such as pilocarpine; (32) cholinesterase inhibitor parasympathomimetics,such as pyridostigmine; (33) α-blocker sympatholytics, such as prazosin;(34) 9-blocker sympatholytics, such as atenolol; (35) adrenergic agonistsympathomimetics, such as albuterol and dobutamine; (36) cardiovascularagents, such as aspirin; (37) i-blocker antianginals, such as atenololand propranolol; (38) calcium-channel blocker antianginals, such asnifedipine and verapamil; (39) nitrate antianginals, such as isosorbidedinitrate (ISDN); (40) cardiac glycoside antiarrhythmics, such asdigoxin; (41) class I antiarrhythmics, such as lidocaine, mexiletine,phenyloin, procainamide, and quinidine; (42) class II antiarrhythmics,such as atenolol, metoprolol, propranolol, and timolol; (43) class IIIantiarrhythmics, such as amiodarone; (44) class IV antiarrhythmics, suchas diltiazem and verapamil; (45) a blocker antihypertensives, such asprazosin; (46) angiotensin-converting enzyme inhibitor (ACE inhibitor)antihypertensives, such as captopril and enalapril; (47) β-blockerantihypertensives, such as atenolol, metoprolol, nadolol, andpropanolol; (48) calcium-channel blocker antihypertensive agents, suchas diltiazem and nifedipine; (49) central-acting adrenergicantihypertensives, such as clonidine and methyldopa; (50) diurecticantihypertensive agents, such as amiloride, furosemide,hydrochlorothiazide (HCTZ), and spironolactone; (51) peripheralvasodilator antihypertensives, such as hydralazine and minoxidil; (52)antilipemics, such as gemfibrozil and probucol; (53) bile acidsequestrant antilipemics, such as cholestyramine; (54) HMG-CoA reductaseinhibitor antilipemics, such as lovastatin and pravastatin; (55)inotropes, such as aminone, dobutamine, and dopamine; (56) cardiacglycoside inotropes, such as digoxin; (57) thrombolytic agents, such asalteplase (TPA), anistreplase, streptokinase, and urokinase; (58)dermatological agents, such as colchicine, isotretinoin, methotrexate,minoxidil, tretinoin (ATRA); (59) dermatological corticosteroidanti-inflammatory agents, such as betamethasone and dexamethasone; (60)antifungal anti-infectives, such as amphotericin B, clotrimazole,miconazole, and nystatin; (61) antiviral anti-infectives, such asacyclovir; (62) antineoplastics, such as fluorouracil (5-FU); (63)electrolytic and renal agents, such as lactulose; (64) loop diuretics,such as furosemide; (65) potassium-sparing diuretics, such astriamterene; (66) thiazide diuretics, such as hydrochlorothiazide(HCTZ); (67) uricosuric agents, such as probenecid; (68) enzymes such asRNase and DNase; (69) thrombolytic enzymes, such as alteplase,anistreplase, streptokinase and urokinase; (70) antiemetics, such asprochlorperazine; (71) salicylate gastrointestinal anti-inflammatoryagents, such as sulfasalazine; (72) gastric acid-pump inhibitoranti-ulcer agents, such as omeprazole; (73) H₂-blocker anti-ulceragents, such as cimetidine, famotidine, nizatidine, and ranitidine; (74)digestants, such as pancrelipase; (75) prokinetic agents, such aserythromycin; (76) fentanyl; (77) hematopoietic antianemia agents, suchas erythropoietin, filgrastim (G-CSF), and sargramostim (GM-CSF); (78)coagulation agents, such as antihemophilic factors 1-10 (AHF 1-10); (79)anticoagulants, such as warfarin; (80) thrombolytic enzyme coagulationagents, such as alteplase, anistreplase, streptokinase and urokinase;(81) hormones and hormone modifiers, such as bromocriptine; (82)abortifacients, such as methotrexate; (83) antidiabetic agents, such asinsulin; (84) oral contraceptives, such as estrogen and progestin; (85)progestin contraceptives, such as levonorgestrel and norgestrel; (86)estrogens such as conjugated estrogens, diethylstilbestrol (DES),estrogen (estradiol, estrone, and estropipate); (87) fertility agents,such as clomiphene, human chorionic gonadatropin (HCG), and menotropins;(88) parathyroid agents such as calcitonin; (89) pituitary hormones,such as desmopressin, goserelin, oxytocin, and vasopressin (ADH); (90)progestins, such as medroxyprogesterone, norethindrone, andprogesterone; (91) thyroid hormones, such as levothyroxine; (92)immunobiologic agents, such as interferon beta-1b and interferongamma-1b; (93) immunoglobulins, such as immune globulin IM, IMIG, IGIMand immune globulin IV, IVIG, IGIV; (94) amide local anesthetics, suchas lidocaine; (95) ester local anesthetics, such as benzocaine andprocaine; (96) musculoskeletal corticosteroid anti-inflammatory agents,such as beclomethasone, betamethasone, cortisone, dexamethasone,hydrocortisone, and prednisone; (97) musculoskeletal anti-inflammatoryimmunosuppressives, such as azathioprine, cyclophosphamide, andmethotrexate; (98) musculoskeletal nonsteroidal anti-inflammatory drugs(NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorlac, andnaproxen; (99) skeletal muscle relaxants, such as baclofen,cyclobenzaprine, and diazepam; (100) reverse neuromuscular blockerskeletal muscle relaxants, such as pyridostigmine; (101) neurologicalagents, such as nimodipine, riluzole, tacrine, trazodone, andticlopidine; (102) anticonvulsants, such as carbamazepine, gabapentin,lamotrigine, phenyloin, and valproic acid; (103) barbiturateanticonvulsants, such as phenobarbital and primidone; (104)benzodiazepine anticonvulsants, such as clonazepam, diazepam, andlorazepam; (105) anti-parkisonian agents, such as bromocriptine,levodopa, carbidopa, and pergolide; (106) anti-vertigo agents, such asmeclizine; (107) opiate agonists, such as codeine, fentanyl,hydromorphone, methadone, tramadol, and morphine; (108) opiateantagonists, such as naloxone; (109) β-blocker anti-glaucoma agents,such as timolol; (110) miotic anti-glaucoma agents, such as pilocarpine;(111) ophthalmic aminoglycoside antiinfectives, such as gentamicin,neomycin, and tobramycin; (112) ophthalmic quinolone anti-infectives,such as ciprofloxacin, norfloxacin, and ofloxacin; (113) ophthalmiccorticosteroid anti-inflammatory agents, such as dexamethasone andprednisolone; (114) ophthalmic nonsteroidal anti-inflammatory drugs(NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapine,haloperidol, and risperidone; (116) benzodiazepine anxiolytics,sedatives and hypnotics, such as clonazepam, diazepam, lorazepam,oxazepam, and prazepam; (117) psychostimulants, such as methylphenidateand pemoline; (118) antitussives, such as codeine; (119)bronchodilators, such as theophylline; (120) adrenergic agonistbronchodilators, such as albuterol; (121) respiratory corticosteroidanti-inflammatory agents, such as dexamethasone; (122) antidotes, suchas flumazenil and naloxone; (123) heavy metal antagonists/chelatingagents, such as penicillamine; (124) deterrent substance abuse agents,such as disulfuram, naltrexone, and nicotine; (125) withdrawal substanceabuse agents, such as bromocriptine; (126) minerals, such as iron,calcium, and magnesium; (127) vitamin B compounds, such ascyanocobalamin (vitamin B₁₂) and niacin (vitamin B₃); (128) vitamin Ccompounds, such as ascorbic acid; (129) vitamin D compounds, such ascalcitriol, and (130) histiamine type drugs such as betahistinehydrochloride.

In some embodiments, compositions disclosed herein include more thanabout 15% pharmaceutically active ingredient by weight, for examplebetween about 15% and about 60%, or between about 20% and about 60%, orbetween about 20% and about 55% by weight. In other embodiments,compositions contemplated herein may include more than about 15% weightcontrolled release excipient such as cross-linked high amylose starch,for example, between about, 15% and about 85%, or about 20% and about85%, or about 20% and about 60%, or about 20% and about 50%, or about30% and about 50% by weight. The composition according to the inventionpreferably comprise from about 15% to about 50% by weight, morepreferably, from about 25% to about 50% active ingredient and from about20% to 60% by weight, more preferably from about 25% to about 50% byweight of controlled release excipient. In a particular embodiment, thisinvention is directed to a composition comprising about 5% to about 50%by weight of active ingredient and about 30% to about 50% by weight ofcross-linked high amylose starch.

Controlled release excipients contemplated herein may vary to a largeextent as is well known to one skilled in the art, provided that aformulation including an excipient has the disclosed release propertiesand/or therapeutic action. Controlled release excipients may includecross-linked starches, hydrogels, celluloses, and/or polymers, and othercontrolled release excipients known to those skilled in the art.

In one embodiment, the controlled release excipient preferably comprisesa cross-linked high amylose starch, for example, where the cross-linkedhigh amylose starch is cross-linked with phosphorus oxychloride and/orcomprises hydroxypropyl side chains. A suitable excipient has beendeveloped by and is available commercially from Labopharm, Inc., Laval,Canada, under the trademark CONTRAMID®. The synthesis of the CONTRAMID®excipient is described, for example, in U.S. Pat. No. 6,607,748, herebyincorporated by reference in its entirety for all purposes. Compositionscontemplated herein may include cross-linked high amylose starchtogether with one or more additional controlled release excipients.

Cross-linking of starch represents a powerful method for modifyingstarch. Usually, starch granules are cross-linked to increase resistanceof the paste to shear or heat. Such chemically cross-linked starchesprovide a desirable smooth texture and possess viscosity stabilitythroughout processing operations and normal shelf life. In someembodiments, cross-linked high amylose starch as contemplated herein maybe gelatinized after cross-linking. In a preferred embodiment,cross-linking high amylose starch may include additional chemicalmodification (e.g., hydroxypropylation) prior to gelatinization.

The cross-linking of high amylose starch may be realized according toprocedures described in the art. For example, cross-linking of amylosecan be carried out in the manner described in Mateescu [BIOCHEMIE 60:535-537 (1978)] by reacting amylose with epichlorohydrin in an alkalinemedium. In the same manner, starch can also be cross-linked with areagent selected from the group consisting of epichlorohydrin, adipicacid anhydride, sodium trimetaphosphate and phosphorous oxychloride orother cross-linking agents including, but not limited to,2,3-dibromopropanol, linear mixed anhydrides of acetic and di- ortribasic carboxylic acids, vinyl sulfone, diepoxides, cyanuric chloride,hexahydro-1,3,5-trisacryloyl-s-triazine, hexamethylene diisocyanate,toluene 2,4-diisocyanate, N,N-methylenebisacrylamide,N,N′-bis(hydroxymethyl) ethyleneurea, mixed carbonic-carboxylic acidanhydrides, imidazolides of carbonic and polybasic carboxylic acids,imidazolium salts of polybasic carboxylic acids, and guanidinederivatives of polycarboxylic acids. The reaction conditions employedwill vary with the type and amount of the cross-linking agent that isused, as well as the base concentration, amount and type of starch.

It is contemplated that starches containing more than about 40% w/wamylose can be used to form cross-linked high amylose starch, e.g., peaand wrinkled pea starch, bean starch, hybrids or genetically modifiedtapioca or potato starch, or any other root, tuber or cereal starch.Preferably, high amylose starch containing about 70% w/w amylose is usedas the base material. For example, high amylose starch, CerestarAmyloGel 03003 (Cerestar U.S.A. Inc.), may be used. In certainformulations, the excipient comprises cross-linked high amylose starchcomprising between about 65% and about 75% by weight amylosecross-linked with phosphorus oxychloride.

The pharmaceutical composition according to the invention optionally canalso comprise pharmaceutically acceptable additives. Such additives caninclude, for example, sugars, such as lactose, glucose and sucrose;other starches, such as corn starch and potato starch; cellulose, andits derivatives, such as sodium carboxymethyl cellulose, ethyl celluloseand cellulose acetate; powdered tragacanth; malt; gelatin; talc;glycols, such as propylene glycol; polyols, such as glycerin, sorbitol,mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyllaurate; agar; buffering agents, such as magnesium hydroxide andaluminum hydroxide; alginic acid; and other non-toxic compatiblesubstances employed in pharmaceutical formulations. Such additives mayalso include colorants and/or taste-masking additives.

For example, the compositions disclosed herein may include any one of amixture of a binding agent, a solubilizing agent, an acidifying agent, apore forming agent, a lubricant, a glidant, as is well known to thoseskilled in the art. Preferred pharmaceutical additives that are used inproviding a composition according to the invention may include, forexample, binding agents that include hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose,dicalcium phosphate, calcium phosphate, microcrystalline cellulose,start or the like, solubilizing agents such as povidone, cetylpyridiniumchloride, or the like, acidifying agents such as alginic acid, citricacid, succinic acid, bile acid or the like, a pore forming agent such assucrose, lactose, mannitol or the like, lubricants such as sodiumstearyl fumarate, magnesium stearate, calcium stearate, stearic acid,hydrogentated vegetable oils or the like and/or glidants such ascolloidal silicon dioxide, talc or the like. Other additives well knownto those skilled in the art may of course be included in the compositionaccording to the invention without departing from the scope and spiritof the present invention.

For example, in one embodiment, the composition may comprise about 10%to 50% by weight active ingredient, for example, tramadol,acetaminophen, betahistine, about 20% to 60% by weight cross-linked highamylase starch (for example, CONTRAMID® cross-linked high amylosestarch), about 10% to 25% by weight hydroxypropylmethylcellulose, about1% to 5% by weight sodium stearyl fumarate, and up to about 1 weightpercent colloidal silicon dioxide.

In an exemplary formulation protocol for producing a 5 kg batch of anexemplary sustained release formulation containing trazodone, CONTRAMID®excipient, hydroxypropylmethyl cellulose, trazodone HCl and sodiumstearyl fumarate are individually weighed and sifted through a 30 meshfilter. Collodial silicon dioxide is weighed and pre-blended withCONTRAMID®, sifted through a 30 mesh filter, and blended for 10-30seconds, for example, 15 seconds to produce d pre-blend.Hydroxypropylmethylcellulose, trazodone and the Contramid®-collodialsilicon dioxide pre-blend, are combined and blended for 5-10 minutes,for example, 7 minutes, to produce a bulk blend. A small portion of theresulting bulk blend is combined with the sodium stearyl fumarate andblended for 20-60 seconds, for example, 30 seconds. The resulting sodiumstearyl fumarate blend is combined with the residual bulk blend, and theresulting mixture blended for about 2-6 minutes, for example, 4 minutes.The final blend is compressed into tablets using a compression pressureof 27 kN. Caplets are formed using a caplet standard concave punch.

The invention will now be illustrated by means of the following exampleswhich are given for the purpose of illustration only and without anyintention to limit the scope of the present invention.

EXAMPLES Example 1

A sustained release 300 mg trazodone containing formulation (denotedFormulation 1) was prepared having the composition set forth in TABLE 1.

TABLE 1 Formulation 1 Tablet Tablet Ingredients (mg) % CONTRAMID ®excipient 200 32.1 Trazodone HCl 300 48.2 HydroxypropylmethylcelluloseK100M 100 16.1 Colloidal silicon dioxide 3 0.5 Sodium stearyl fumarate 91.4 Opadry II, Pink 85F94306 10.4 1.7 Total 622.4 100

Formulation 1 was compressed into tablets and analyzed. The in vitrorelease kinetics of the intact dosage form and subdivided (bisected)dosage forms created by breaking the intact dosage form into two weremeasured as follows.

Briefly, the in vitro release kinetics of Formulation 1 were measuredusing the U.S.P. paddle method (apparatus type II as described in U.S.P.XXVI) at 150 revolutions per minute, at 37±0.5° C., in 900 mL ofhydrochloride/sodium chloride pH 1.2 solution (acid stage) followedafter one hour by 900 mL of sodium phosphate monobasic buffer pH 6.0(buffer stage). The in vitro dissolution profiles, as shown in FIG. 2,show that in this formulation, the release profiles of both the intactand bisected tablet have a similarity factor of 73.9 and a differencefactor of 6.1.

In addition, the effect of different score depths on release kineticswere measured. The in vitro release kinetics of two forms of the tablethaving 23% scoring and 95% scoring are shown in FIGS. 3 and 4,respectively. FIGS. 3 and 4 demonstrate that the in vitro releaseprofile of this formulation (either of the intact tablet or thesubdivided tablet created by breaking the intact tablet along the score)is not substantially affected by scoring depth.

Example 2

A sustained release 150 mg trazodone containing formulation (denotedFormulation 2) was prepared having the composition set forth in TABLE 2.

TABLE 2 Formulation 2 Tablet Tablet Ingredients (mg) % CONTRAMID ®excipient 252 46.8 Trazodone HCl 150 27.8 HydroxypropylmethylcelluloseK100M 126 23.4 Colloidal silicon dioxide 3 0.5 Sodium stearyl fumarate 81.5 Total 540 100

Formulation 2 was compressed into tablets. Mass uniformity testing onthis formulation using the U.S.P. test limit of uniformity to achieve anRSD below 6% indicates that the minimum tablet hardness needed toachieve mass uniformity is about 110N (see, FIG. 5).

The in vitro release kinetics of the intact dosage form and subdivided(bisected) dosage forms created by breaking the intact dosage form intotwo were measured as described in Example 1. The in vitro dissolutionprofiles, as shown in FIG. 6, show that in this formulation, the releaseprofiles for both the intact and bisected tablet have a similarityfactor of 73.4 and a difference factor of 6.4.

Example 3

A sustained release 300 mg tramadol containing formulation (denotedFormulation 3) was prepared having the composition set forth in TABLE 3.

TABLE 3 Formulation 3 Tablet Tablet Ingredients (mg) % CONTRAMID ®excipient 200 32.7 Tramadol HCl 300 49.0 Hydroxylpropylmethyl celluloseK100M 100 16.3 Colloidal silicon dioxide 3 0.5 Sodium stearyl fumarate 91.5 Total 612 100

The above formulation was compressed into tablets. The in vitro releasekinetics of the intact dosage form and subdivided (bisected) dosageforms created by breaking the intact dosage form into two were measuredas follows. Briefly, the in vitro release kinetics of the intact andbisected tablets were measured using the U.S.P. basket method (apparatustype I as described in U.S.P. XXVI) at 100 revolutions per minute, at37±0.5° C., in 900 mL of sodium phosphate monobasic buffer pH 6.8. Thein vitro dissolution profiles, as shown in FIG. 7, show that in thisformulation, the release profiles for both the intact and bisectedtablet have a similarity factor of 58.3 and a difference factor of 14.2.

Example 4

A sustained release 300 mg acetaminophen containing formulation (denotedFormulation 4) can be prepared having the composition set forth in TABLE4.

TABLE 4 Formulation 4 Tablet Tablet Ingredients (mg) % CONTRAMID ®excipient 200 32.1 Acetaminophen 300 48.2 Hydroxylpropylmethyl celluloseK100M 100 16.1 Colloidal silicon dioxide 3 0.5 Sodium stearyl fumarate 91.4 Total 612 100

It is contemplated that with this formulation, when compressed intotablets, the intact and bisected dosage forms will display substantiallysimilar in vitro release kinetics.

Example 5

A sustained release 48 mg betahistine containing formulation (denotedFormulation 5) can be prepared having the composition set forth in TABLE5.

TABLE 5 Formulation 5 Tablet Tablet Ingredients (mg) % CONTRAMID ®excipient 168 54.90 Betahistine HCl 48 15.69 Hydroxylpropylmethylcellulose K100M 84 27.45 Colloidal silicon dioxide 1.5 0.49 Sodiumstearyl fumarate 4.5 1.47 Total 306 100.00

It is contemplated that with this formulation, when compressed intotablets, the intact and bisected dosage forms will display substantiallysimilar in vitro release kinetics.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent and scientific documentsreferred to herein is incorporated by reference for all purposes.

EQUIVALENTS

Although the present invention has been illustrated by means ofpreferred embodiments thereof, it is understood that the inventionintends to cover broad aspects thereof without departing from the spiritand scope of the invention as defined in the appended claims.

What is claimed is:
 1. A solid, monolithic sustained releasepharmaceutical composition having an outer surface, the compositioncomprising: a. a sustained release matrix having a solvent accessiblesurface, the matrix comprising from about 20% to about 60% by weight ofcross-linked high amylose starch; and b. an effective amount of at leastone pharmaceutically active agent disposed within the matrix, thecomposition having a hardness in the range of from about 100 N to about350 N, and the outer surface of the composition defining a score thatpermits the composition to be fractured along the score to produce atleast two subunits, wherein at least one of the subunits and thecomposition from which it was derived have substantially the samerelease kinetics of the active agent disposed therein, and wherein atleast one of the subunits created by fracturing the composition has anew solvent accessible surface that is capable of forming a barrier uponcontact with a solvent.
 2. The composition of claim 1, wherein thecomposition, when administered to a mammal, achieves an effective plasmaconcentration of the active agent from at least about 1 hour to at leastabout 24 hours after initial administration.
 3. The composition of claim1, wherein at least one of the subunits and the composition from whichit was derived have dissolution profiles of the active agent that have asimilarity factor of at least 50%.
 4. The composition of claim 3,wherein the similarity factor is at least 55%.
 5. The composition ofclaim 1, wherein the composition has a hardness in the range of fromabout 100 N to about 180 N.
 6. The composition of claim 1, wherein thesubunits and the intact composition from which they are derived arebioequivalent.
 7. The composition of claim 1 comprising from about 20%to about 50% by weight of the active ingredient and from about 20% toabout 50% by weight of the starch.
 8. The composition of claim 7comprising from about 35% to about 50% by weight of the activeingredient and from about 20% to about 50% by weight of the starch. 9.The composition of claim 1, wherein the starch is crosslinked withphosphorus oxychloride.
 10. The composition of claim 1, wherein thestarch comprises hydroxypropyl side chains.